659 Packaging and Storage Requirements, · Containers—Glass 〈660〉, Plastic Packaging Systems...
Transcript of 659 Packaging and Storage Requirements, · Containers—Glass 〈660〉, Plastic Packaging Systems...
BRIEFING
⟨659⟩ Packaging and Storage Requirements, USP 42 page 6801 and
PF 44(4) [July–Aug. 2018]. The General Chapters—Packaging and
Distribution Expert Committee has canceled the PF 44(4) proposal and is
now proposing the following revision. The purpose of the revisions will be to
provide a delayed extension of the requirements specified in Plastic Materials
of Construction ⟨661.1⟩ and Plastic Packaging Systems for Pharmaceutical
Use ⟨661.2⟩, which otherwise were to become applicable on May 1, 2020
through this chapter, to enable early adoption of the requirements in ⟨661.1⟩
and ⟨661.2⟩ at any time during the implementation delay period in lieu of
meeting the reinstated Plastic Packaging Systems and Their Materials of
Construction ⟨661⟩ requirements.
The specific revisions are as follows:
1. Delay until December 1, 2025 the implementation of the new
requirements of ⟨661.1⟩ and ⟨661.2⟩ as currently specified in this
chapter.
2. To make ⟨661⟩, as referenced in this chapter, applicable until
November 30, 2025.
3. In this chapter, clarify that early adoption of the requirements of
⟨661.1⟩ and ⟨661.2⟩ is permitted by USP, and that packaging systems
in compliance with these requirements in advance of December 1,
2025 will no longer need to comply with ⟨661⟩ requirements to be
considered by USP to be in conformance with the USP–NF.
4. For the "Small-volume injection" and "Large-volume injection"
definitions, it was clarified that terms are also referred to as "Small-
volume parenteral" and "Large-volume parenteral", respectively.
Additionally, minor editorial changes have been made to update the
chapter to current USP style.
(GCPD: D. Hunt.)
Correspondence Number—C201835
⟨659⟩ PACKAGING AND STORAGE REQUIREMENTS 1
Change to read: 2
(A portion of the Associated Components section of this chapter will 3
become official on May 1, 2019, and a portion of the Packaging 4
section of this chapter will become official on May 1, 5
2020,▲December 1, 2025▲ (USP 1-Aug-2020) as indicated. Early adoption of 6
the requirements in this chapter and Plastic Materials of 7
Construction ⟨661.1⟩ and Plastic Packaging Systems for 8
Pharmaceutical Use ⟨661.2⟩ are permitted by USP.) 9
INTRODUCTION 10
The purpose of this chapter is to provide packaging definitions, auxiliary 11
packaging information, and storage condition definitions relevant to the 12
storage and distribution of active ingredients, excipients, and medical 13
products, such as pharmaceuticals, devices, combination products (e.g., 14
drug-eluting stents), and dietary supplements. 15
Change to read: 16
PACKAGING 17
Packaging materials must not interact physically or chemically with a 18
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packaged article in a manner that causes its safety, identity, strength,
quality, or purity to fail to conform to established requirements. ▲Any
plastic material used to construct a Packaging system must meet the
applicable requirements of Plastic Materials of Construction ⟨661.1⟩.▲1-
May-2020 All Packaging systems must meet the applicable requirements
specified in
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Containers—Glass ⟨660⟩, Plastic Packaging Systems and Their Materials of
Construction ⟨661⟩, ▲Plastic Packaging Systems for Pharmaceutical Use
⟨661.2⟩,▲1-May-2020 and Auxiliary Packaging Components ⟨670⟩. All elastomeric
closures must meet the applicable requirements in Elastomeric Closures
for Injections ⟨381⟩. 28
Every monograph in USP–NF must have packaging and storage 29
requirements. For the packaging portion of the statement, the choice of 30
containers is provided in this chapter. For active pharmaceutical 31
ingredients (APIs), the choice would be a tight, well-closed, or, where 32
needed, light-resistant container. For excipients, given their typical 33
presentation as large-volume commodity items (Packaging systems 34
ranging from drums to tank cars), a well-closed container is an appropriate 35
default requirement. Articles must be protected from moisture, freezing, 36
and excessive heat (see General Definitions) when no specific directions or 37
limitations are provided. 38
The compendial requirements for the use of specified containers apply also 39
to articles packaged by Dispensers, Repackagers, or other individuals, 40
unless otherwise indicated in the individual drug product monograph. 41
POISON PREVENTION PACKAGING ACT 42
This act, which is administered by the United States Consumer Product 43
Safety Commission (CPSC), requires special packaging for most human 44
oral prescription drugs, oral controlled drugs, certain non-oral prescription 45
drugs, certain dietary supplements, and many over-the-counter (OTC) 46
drug preparations, to protect the public from personal injury or illness 47
from misuse of these preparations [16 Code of Federal Regulations (CFR) 48
§1700.14].49
The primary packaging of substances regulated under the Poison Prevention 50
Packaging Act (PPPA) must comply with the special packaging standards 51
(16 CFR §1700.15). These apply to all packaging types, including 52
reclosable, non-reclosable, and unit-dose types. 53
Special packaging is not required for drugs dispensed within a hospital 54
setting for inpatient administration. Also, special packaging does not need 55
to be used by manufacturers and packagers of bulk-packaged prescription 56
drugs that will be repackaged by the pharmacist. PPPA-regulated 57
prescription drugs may be dispensed in non-Child-resistant packaging 58
upon the request of the purchaser or when directed in a legitimate 59
prescription [15 United States Code (USC) §1473]. 60
Manufacturers or packagers of PPPA-regulated OTC preparations are allowed 61
to package one size in non-Child-resistant packaging as long as popular-62
size, special packages are also supplied. The non-Child-resistant packaging 63
requires special labeling (16 CFR §1700.5). 64
TEMPERATURE AND STORAGE 65
Specific directions are stated in some monographs with respect to storage 66
conditions (e.g., the temperature or humidity) at which an article must be 67
stored and shipped. Such directions apply except where the label on the 68
article has different storage conditions that are based on stability studies. 69
Where no specific directions or limitations are provided in the article's 70
labeling, articles must be protected from moisture, freezing, and excessive 71
heat, and, where necessary, from light during shipping and distribution. 72
Drug substances are exempt from this standard. 73
Change to read: 74
GENERAL DEFINITIONS 75
Packaging Definitions 76
Packaging system (also referred to as a Container–closure system): The 77
sum of Packaging components and materials that together contain and 78
protect the article. This includes Primary packaging components as well as 79
Secondary packaging components when such components are required to 80
provide additional protection. 81
Container: A receptacle that holds an intermediate compound, API, 82
excipient, or dosage form, and is in direct contact with the article (e.g., 83
ampules, vials, bottles, syringes, and pen injectors). 84
Closure: A material that seals an otherwise open space of a Container and 85
provides protection for the contents. It also provides access to the contents 86
of the Container (e.g., screw caps and stoppers). 87
Packaging component: Any single part of the Package or Container–88
closure system, including: the Container (e.g., ampules, syringes, vials, and 89
bottles); Closures (e.g., screw caps and stoppers); ferrules and overseals; 90
Closure liners (e.g., tube cartridge liners); inner seals; administration ports; 91
overwraps; administration accessories; labels; cardboard boxes; and shrink 92
wrap. 93
Primary packaging component: A Packaging component that is in direct 94
contact with or may come into direct contact with the article. 95
Secondary packaging component: A Packaging component that is in 96
direct contact with a Primary packaging component and may provide 97
additional protection for the article. 98
Tertiary packaging component: A Packaging component that is in direct 99
contact with a Secondary packaging component and may provide additional 100
protection for the article during transportation and/or storage. 101
Ancillary component: A component or entity that may come into contact 102
with a Tertiary packaging component during the distribution, storage, and/or 103
transportation of the packaged article (e.g., pallets, skids, and shrink wrap). 104
Associated component: A Packaging component that is typically intended 105
to deliver the drug article to the patient but is not stored in contact with the 106
article for its entire shelf life (e.g., spoons, Dosing cups, and dosing 107
syringes). 108
Materials of construction: The materials (e.g., glass, plastic, elastomers, 109
and metal) of which a Packaging component consists. 110
Small-volume injection ▲(also referred to as▲ (USP 1-Aug-2020) Small-volume 111
parenteral): An injectable dosage form that is packaged in Containers 112
labeled as containing 100 mL or less. 113
Large-volume injection ▲(also referred to as▲ (USP 1-Aug-2020) Large-volume 114
parenteral): An injectable dosage form that is packaged in Containers 115
labeled as containing more than 100 mL. 116
Child-resistant packaging: A Packaging system designed or constructed to 117
meet CPSC standards pertaining to opening by children (16 CFR §1700.20 et 118
seq. and 16 CFR §1700.15). 119
Senior-friendly packaging: A Packaging system designed or constructed 120
to meet CPSC standards pertaining to opening by senior adults (16 CFR 121
§1700.15 and 16 CFR §1700.20). 122
Restricted delivery system: A Packaging system designed or constructed 123
to restrict (control) the amount of the drug product that may be delivered in 124
order to limit unintended access by children and other similarly vulnerable 125
populations. Restricted delivery systems should meet and may exceed CPSC 126
standards for special packaging [Child-resistant and Senior-friendly 127
packaging (16 CFR §1700.15 et seq.)]. For oral medicinal liquids, surface 128
and flow characteristics vary. It is the responsibility of the manufacturer to 129
ensure that all components of the Restricted delivery system provide the 130
intended safety protection. One component of the Restricted delivery system 131
is the flow restrictor, which is a Packaging component that restricts the flow 132
of liquid. The flow restrictor may be used as part of a Restricted delivery 133
system or as an adaptor to facilitate use of a measuring device for oral 134
medicinal liquids. A flow restrictor should not compromise CPSC standards 135
for special packaging [Child-resistant and Senior-friendly packaging (16 CFR 136
§1700.15 et seq.)]. 137
Tamper-evident packaging: A Packaging system that may not be 138
accessed without obvious destruction of the seal or some portion of the 139
Packaging system. Tamper-evident packaging must be used for sterile drug 140
products intended for ophthalmic or otic use, except where 141
extemporaneously compounded for immediate dispensing on prescription. 142
Drug products intended for sale without prescription are also required to 143
comply with the Tamper-evident packaging and labeling requirements of the 144
FDA where applicable (21 CFR §221.132). Preferably, the immediate 145
Container and/or the outer Container or protective packaging used by a 146
manufacturer or distributor for all dosage forms that are not specifically 147
exempt is designed to show evidence of any tampering with the contents. 148
Reclosable packaging: A package that after it has been initially opened is 149
capable of being reclosed with a similar degree of security and is capable of 150
being used a sufficient number of times to dispense the total contents 151
without loss of security. Reclosable packaging may incorporate child-152
resistance capabilities. 153
Non-reclosable packaging: A package or part of a package that cannot be 154
closed again after all or part of the contents have been removed. Examples 155
of Non-reclosable packaging are blisters, sachets, strips, and other Single-156
unit containers. Non-reclosable packaging may include cold-formed foil 157
blisters, foil strip packs, and polyvinyl chloride (PVC)/Aclar combining 158
multilayer materials that are thermo-formed or cold-formed foil blisters. 159
Non-reclosable packaging may be child resistant depending on the intended 160
use and place of use. Household non-reclosables are subject to the PPPA as 161
defined in 16 CFR §1700.14. 162
Hermetic container: A Container–closure system that is impervious to air 163
or any other gas under the ordinary or customary conditions of handling, 164
shipment, storage, and distribution. 165
Tight container: A Container–closure system that protects the contents 166
from contamination by extraneous liquids, solids, or vapors; from loss of the 167
article; and from efflorescence, deliquescence, or evaporation under the 168
ordinary or customary conditions of handling, shipment, storage, and 169
distribution, and is capable of tight reclosure. Where a tight container is 170
specified, it may be replaced by a hermetic container for a single dose of an 171
article. [NOTE—Where packaging and storage in a tight container or well-172
closed container is specified in the individual monograph, the container used 173
for an article when dispensed on prescription meets the requirements in 174
Containers—Performance Testing ⟨671⟩.] 175
Well-closed container: A Container–closure system that protects the 176
contents from contamination by extraneous solids and from loss of the 177
article under the ordinary or customary conditions of handling, shipment, 178
storage, and distribution. See ⟨671⟩. 179
Light-resistant container: A Container–closure system that protects the 180
contents from the effects of light by virtue of the specific properties of the 181
material of which it is composed, including any coating applied to it. A clear 182
and colorless or a translucent container may be made light-resistant by 183
means of an opaque covering or by use of secondary packaging, in which 184
case the label of the container bears a statement that the opaque covering 185
or secondary packaging is needed until the articles are to be used or 186
administered. Where it is directed to “protect from light” in an individual 187
monograph, preservation in a light-resistant container is intended. See 188
Plastic Packaging Systems for Pharmaceutical Use ⟨661.2⟩, Functionality, 189
Spectral Transmission Requirements for Light-Resistant 190
Containers▲Components and Systems.▲ (USP 1-Aug-2020) 191
Equivalent container–closure system: A Container–closure system that 192
is as protective as or more protective than the original manufacturer’s 193
Packaging system in terms of moisture vapor transmission rate, oxygen 194
transmission, light transmission, and compatibility. System equivalency 195
extends to any special protective materials, such as those for seals or 196
desiccants associated with the original Packaging system. 197
Table 1. Packaging Systems Definitions: Injection versus 198
Noninjection 199
Injection Noninjection
Multiple-dose Multiple-unit
Single-dose Single-unit
— Unit-dose
— Unit-of-use
Pharmacy bulk package —
Imaging bulk package —
200
Injection Packaging Systems 201
Multiple-dose container (also referred to as Multi-dose): A Container–202
closure system that holds a sterile medication for parenteral administration 203
(injection or infusion) that has met antimicrobial effectiveness testing 204
requirements, or is excluded from such testing requirements by FDA 205
regulation. A Multiple-dose container is intended to contain more than one 206
dose of a drug product. When space permits, a Multiple-dose container is 207
labeled as such. Multiple-dose containers are generally expected to contain 208
30 mL or less of medications. The beyond-use date for an opened or entered 209
(e.g., needle-punctured) Multiple-dose container is 28 days unless otherwise 210
specified by the manufacturer on the label. An example of a Multiple-dose 211
container is a vial. 212
Single-dose container: A Container–closure system that holds a sterile 213
medication for parenteral administration (injection or infusion) that is not 214
required to meet the antimicrobial effectiveness testing requirements. A 215
Single-dose container is designed for use with a single patient as a single 216
injection/infusion.1 When space permits, a Single-dose container is labeled 217
as such and should include on the label appropriate discard statements. 218
Examples of Single-dose containers are vials, ampules, and prefilled 219
syringes. 220
Pharmacy bulk package: A Container–closure system of a sterile 221
preparation for parenteral use that contains many single doses. The contents 222
are intended for use in a pharmacy admixture program and are restricted to 223
the preparation of admixtures for infusion or, through a sterile transfer 224
device, for the filling of empty sterile syringes. The Closure must be 225
penetrated only one time after constitution, if necessary, with a suitable 226
sterile transfer device or dispensing set that allows measured dispensing of 227
the contents. The Pharmacy bulk package is to be used only in a suitable 228
work area such as a laminar flow hood (or an equivalent clean-air 229
compounding area). Designation as a Pharmacy bulk package is limited to 230
injection, for injection, or injectable emulsion dosage forms as defined in 231
Nomenclature ⟨1121⟩, General Nomenclature Forms.Pharmacy bulk 232
packages, although containing more than one single dose, are exempt from 233
the Multiple-dose container volume limit of 30 mL and the requirement that 234
they contain a substance or suitable mixture of substances to prevent the 235
growth of microorganisms. See Labeling ⟨7⟩ for labeling requirements. 236
Imaging bulk package: A container of a sterile preparation for parenteral 237
use that contains many single doses of a contrast agent (medical imaging 238
drug product) for use with a medical imaging device. The contents are 239
restricted to use in direct conjunction with a device with features to mitigate 240
the risk of cross-contamination (i.e., an automated contrast injection system 241
or contrast management system approved or cleared for use with an 242
Imaging bulk package). The sterility assurance of the Imaging bulk package 243
contents in part is dependent upon the automated contrast injection system 244
or the contrast management system.The Imaging bulk package is to be used 245
only in a room designated for radiological procedures that involve 246
intravascular administration of a contrast agent. Using aseptic technique, the 247
Imaging bulk package closure must be penetrated only one time with a 248
suitable sterile component of the automated contrast injection system or 249
contrast management system. If the integrity of the Imaging bulk package 250
and the delivery system cannot be assured through direct continuous 251
supervision, the Imaging bulk package and all associated disposables for the 252
automated contrast injection system or contrast management system should 253
be discarded.Designation as an Imaging bulk package is limited to injection, 254
for injection, or injectable emulsion dosage forms as defined in 255
Nomenclature ⟨1121⟩, General Nomenclature Forms. Imaging bulk packages, 256
although containing more than one single dose, are exempt from the 257
multiple-dose container volume limit of 30 mL. The contents of the Imaging 258
bulk package must have demonstrated the ability to limit the growth of 259
microorganisms over the labeled period of use.Where a container is offered 260
as an Imaging bulk package, the label must: 1) state prominently “Imaging 261
Bulk Package” and, in juxtaposition with this statement, include the following 262
use statement: “For use only with an automated contrast injection system or 263
contrast management system approved or cleared for use with this contrast 264
agent in this Imaging Bulk Package”; 2) bear a statement limiting the time 265
frame in which the container may be used once it has been entered, 266
provided it is held under the labeled storage conditions; and 3) bear the 267
statement, “See drug and device labeling for information on devices 268
indicated for use with this Imaging Bulk Package and techniques to help 269
assure safe use”. 270
Noninjection Packaging Systems 271
Multiple-unit container: A Container–closure system that permits 272
withdrawal of successive portions of a noninjection article without changing 273
the safety, strength, quality, or purity of the remaining portion (e.g., bottle 274
of capsules, tablets, and oral or topical liquids). 275
Single-unit container: A Container–closure system that holds a quantity of 276
a noninjection article intended for administration as a single dose or a single 277
finished device intended for use promptly after the Packaging system is 278
opened. 279
Unit-dose container: A single-unit Container–closure system for an article 280
intended for administration by other than the parenteral route as a single 281
dose. 282
Unit-of-use container: A Container–closure system that contains a specific 283
quantity of an article that is intended to be dispensed as such without 284
further modification except for the addition of appropriate labeling (see ⟨7⟩). 285
It is not permitted to repackage Unit-of-use containers for sale. 286
Miscellaneous 287
Repackaging: The act of removing a drug product from the original 288
manufacturer’s Packaging system and placing it into another Packaging 289
system, usually one of smaller size. 290
Repackager: A firm that repackages drug products or medical devices for 291
distribution (e.g., for resale to distributors, hospitals, or pharmacies). For 292
drug products, this applies to a function that is beyond the regular practice 293
of a pharmacy. The distribution is not patient-specific, in that there are no 294
prescriptions. Repackagers and relabelers of medical devices are also 295
required to register and list and meet the provisions described in 21 CFR 296
§807. 297
Contract packager/contract repackager: A firm that is contracted by 298
another organization, such as a manufacturer, to package bulk into a 299
marketed Container of a drug product. A Contract packager does not take 300
ownership from the manufacturer and generally receives the assigned 301
expiration date from the manufacturer. 302
Dispenser: A licensed or registered practitioner who is legally responsible 303
for providing the patient with a preparation that is in compliance with a 304
prescription or a medication order and contains a specific patient label. In 305
addition, dispensers may prepare limited quantities in anticipation of a 306
prescription or medication order from a physician. Dispensers are governed 307
by the board of pharmacy of the individual state. The terms “dispenser” and 308
“pharmacy” are used interchangeably. 309
Beyond-use date: See ⟨7⟩. 310
Expiration date: See ⟨7⟩. 311
Black closure system or black bands: The use of a Black closure system 312
on a vial (e.g., a black cap overseal and a black ferrule to hold the 313
elastomeric closure) or the use of a Black band or series of bands above the 314
constriction on an ampule is prohibited, except for Labeling ⟨7⟩, Labels and 315
Labeling for Injectable Products, Potassium Chloride for Injection 316
Concentrate. 317
INJECTION PACKAGING 318
Packaging for sterile products intended for injection must be validated as 319
meeting the containment and protection requirements that are essential 320
for maintaining the article's quality. Refer to Package Integrity 321
Evaluation—Sterile Products ⟨1207⟩, Package Integrity Testing in the 322
Product Life Cycle—Test Method Selection and Validation ⟨1207.1⟩, 323
Package Integrity Leak Test Technologies ⟨1207.2⟩, and Package Seal 324
Quality Test Technologies ⟨1207.3⟩ for further information regarding sterile 325
product container–closure integrity testing and validation. Closures for 326
Multiple-dose containers permit the withdrawal of the contents without 327
removal or destruction of the Closure. The Closure permits penetration by 328
a needle and, upon withdrawal of the needle, closes at once, protecting 329
the contents against contamination. Refer to ⟨381⟩ for Closure reseal tests 330
that are useful for screening multiple-dose Closures for their reseal 331
properties. Additional testing may be needed to ensure that the specific 332
Closure selected for a product package is able to prevent loss of product 333
contents and microbial contamination under anticipated conditions of 334
multiple entry and use. Piggyback Packaging systems are usually 335
intravenous infusion Container–closure systems that are used to 336
administer a second infusion through a connector of some type or an 337
injection port on the administration set of the first fluid, thereby avoiding 338
the need for another injection site on the patient's body. Piggyback 339
Packaging systems also are known as secondary infusion containers. 340
The volume of injection in a Single-dose container provides the amount 341
specified for one-time parenteral administration, and in no case is more 342
than sufficient to permit the withdrawal and administration of 1 L. 343
Preparations intended for intraspinal, intracisternal, or peridural 344
administration are packaged in Single-dose containers only. Unless 345
otherwise specified in the individual monograph, a Multiple-dose container 346
contains a volume of injection sufficient to permit the withdrawal of NMT 347
30 mL. 348
The following injections are exempt from the 1-L restriction of the foregoing 349
requirements relating to packaging: 350
Injections packaged for extravascular use as irrigation solutions or 351
peritoneal dialysis solutions 352
Injections packaged for intravascular use as parenteral nutrition or as 353
replacement or substitution fluid to be administered continuously 354
during hemofiltration 355
Injections packaged for intravascular use that may be used for intermittent, 356
continuous, or bolus replacement fluid administration during hemodialysis 357
or other procedures, unless excepted above, must conform to the 1-L 358
restriction. Injections labeled for veterinary use are exempt from the 359
packaging and storage requirements concerning the limitation to single-360
dose Packaging systems and the limitation on the volume of Multiple-dose 361
containers. 362
Packaging for Constitution 363
Containers, including the Closures, for dry solids intended for injection must 364
not interact physically or chemically with the preparation in any manner 365
that alters the strength, quality, or purity beyond the official requirements 366
under the ordinary or customary conditions of handling, shipment, 367
storage, sale, and use. A Packaging system for a sterile solid permits the 368
addition of a suitable solvent and withdrawal of portions of the resulting 369
solution or suspension in such manner that the sterility of the product is 370
maintained. Where the assay in a monograph provides a procedure for the 371
sample solution, in which the total withdrawable contents are to be 372
withdrawn from a Single-dose container with a hypodermic needle and 373
syringe, the contents are to be withdrawn as completely as possible into a 374
dry hypodermic syringe of a rated capacity not exceeding 3 times the 375
volume to be withdrawn and fitted with a 21-gauge needle NLT 2.5 cm (1 376
inch) in length. Care must be taken to expel any air bubbles, and the 377
contents are then discharged into a Container for dilution and assay. 378
Change to read: 379
MEDICAL GAS PACKAGING 380
Gas cylinder: A metallic Packaging system constructed of steel or aluminum 381
and designed to hold medical gases under pressure; these gases may 382
include: Carbon Dioxide USP, Helium USP, Medical Air USP, nitric oxide,▲▲ (USP 383
1-Aug-2020)Nitrous Oxide USP, Nitrogen NF, and Oxygen USP. As a safety 384
measure, for carbon dioxide, helium, medical air, nitrous oxide, and oxygen, 385
the Pin Index Safety System of matched fittings is recommended for 386
cylinders of Size E or smaller. 387
Change to read: 388
ASSOCIATED COMPONENTS 389
Many Associated Components are graduated for measurement and dose 390
administration. Associated Components can be packaged with the drug 391
product or sold and purchased separately. It is the responsibility of the 392
manufacturer to ensure that the appropriate measurement and dosing 393
component is provided or that a general purpose component, such as 394
those described in this section, is specified for delivering the appropriate 395
amount/dose with the intended accuracy. Liquid preparations have unique 396
surface and flow characteristics. Consequently, the volume delivered from 397
a measurement/dosing component may vary for each preparation. 398
The graduated Associated Components described in this section are for 399
general use and should be composed of safe materials. Graduated 400
markings should be legible, indelible, and on an extraoral surface that 401
does not contact the product. 402
▲The associated volume markings must be in metric units only and limited to 403
a single measurement scale that corresponds with the dosing instructions 404
on the OTC or prescription container label (see Prescription Container 405
Labeling ⟨17⟩). Under expected conditions of use, the volume error 406
incurred in measuring liquids for individual dose administration by means 407
of such graduated components should be NMT 10% of the indicated 408
amount of the liquid preparation with which the graduated component will 409
be used.▲ (Official 1-May-2019) 410
Dosing cup: A measuring device consisting of a small cup that may be 411
packaged with oral liquid articles. 412
Dosing spoon: A measuring device consisting of a bowl and handle that 413
may be packaged with oral liquid articles. The handle may be a graduated 414
tube. 415
Medicine dropper: A measuring device consisting of a transparent or 416
translucent barrel or tube that is generally fitted with a collapsible bulb. It 417
may be packaged with oral liquid articles. 418
Oral syringe: A measuring device consisting of a plunger and barrel made 419
of transparent or translucent plastic material and a seal on the end. It may 420
be packaged with oral liquid articles. The syringe should deliver a measured 421
amount of a liquid drug product. 422
TEMPERATURE AND STORAGE DEFINITIONS 423
Freezer: A place in which the temperature is controlled between −25° and 424
−10° (−13° and 14° F). It is noted that, in some instances, articles may 425
have a recommended storage condition below −20° (−4° F). In such cases, 426
the temperature of the storage location should be controlled to ±10°. 427
Refrigerator: A cold place in which the temperature is controlled between 428
2° and 8° (36° and 46° F). 429
Cold: Any temperature not exceeding 8° (46° F). 430
Cool: Any temperature between 8° and 15° (46° and 59° F). [NOTE—An 431
article for which storage in a cool place is directed may, alternatively, be 432
stored and shipped as refrigerated, unless otherwise specified by the 433
individual monograph.] 434
Room temperature (also referred to as Ambient temperature): The 435
temperature prevailing in a working environment. 436
Controlled room temperature: The temperature maintained 437
thermostatically that encompasses the usual and customary working 438
environment of 20°–25° (68°–77° F). The following conditions also 439
apply.Mean kinetic temperature not to exceed 25°. Excursions between 15° 440
and 30° (59° and 86° F) that are experienced in pharmacies, hospitals, and 441
warehouses, and during shipping are allowed. Provided the mean kinetic 442
temperature does not exceed 25°, transient spikes up to 40° are permitted 443
as long as they do not exceed 24 h. Spikes above 40° may be permitted 444
only if the manufacturer so instructs.Articles may be labeled for storage at 445
“controlled room temperature” or at “20°–25°”, or other wording based on 446
the same mean kinetic temperature [see also Good Storage and Distribution 447
Practices for Drug Products ⟨1079⟩, Quality Management System, 448
Environmental Management System, Mean Kinetic Temperature (MKT) 449
Calculation].An article for which storage at Controlled room temperature is 450
directed may, alternatively, be stored and shipped in a cool place or 451
refrigerated, unless otherwise specified in the individual monograph or on 452
the label. 453
Warm: Any temperature between 30° and 40° (86° and 104° F). 454
Excessive heat: Any temperature above 40° (104° F). 455
Dry place: A place that does not exceed 40% average relative humidity at 456
20° (68° F) or the equivalent water vapor pressure at other temperatures. 457
The determination may be made by direct measurement at the place. 458
Determination is based on NLT 12 equally spaced measurements that 459
encompass either a season, a year, or, where recorded data demonstrate, 460
the storage period of the article. There may be values of up to 45% relative 461
humidity provided that the average value does not exceed 40% relative 462
humidity. Storage in a Container validated to protect the article from 463
moisture vapor, including storage in bulk, is considered a Dry place. 464
Protect from freezing: The Container label will bear an appropriate 465
instruction to protect the article from freezing in cases where freezing 466
exposes an article to loss of strength or potency or to destructive alteration 467
of its characteristics. These risks are present in addition to the risk that the 468
Container may break if exposed to freezing temperatures. 469
Protect from light: Where light subjects an article to loss of strength or 470
potency or to destructive alteration of its characteristics, the Container label 471
bears an appropriate instruction to protect the article from light. The article 472
must be packaged in a light-resistant Container. 473
474
1 Exceptions may be considered only under conditions described in Pharmaceutical Compounding—Sterile Preparations ⟨797⟩. 475